Dysfunction of insulin-AKT-UCP1 signalling inhibits transdifferentiation of human and mouse white preadipocytes into brown-like adipocytes

Abstract

The mechanism of insulin signaling on browning of white preadipocytes remains unclear. Human and mouse primary subcutaneous white preadipocytes (hsASCs and WT lean and obese msASCs, respectively) were induced to transdifferentiate into beige adipocytes under conditions of intact or blocked insulin signaling, respectively. Level of phosphoinositide-3-kinase (PI3K) after induction of beige adipocytes under conditions of normal insulin signaling, phosphorylated protein kinase B (pAKT), peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC-1α), zinc-fifinger transcriptional factor PRD1-BF1-RIZ1 homologous domain-containing protein 16 (PRDM16), uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein beta (C/EBPβ) were significantly increased. Conversely, when insulin signaling is incompletely inhibited, the expression of the thermogenic and adipogenic factors is significantly reduced, with obvious impairment of adipogenesis. However, phosphorylation level of adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) and expression level of sirtuin type 1 (SIRT1) had increased. These white preadipocytes from different donors showed similar dynamic change in morphology and molecular levels during the browning. The present data indicate that insulin signaling plays a important role in regulation of browning of hsASCs and msASCs through PI3K-AKT-UCP1 signaling pathway. The insulin-AMPK-SIRT1 pathway was also involved in the adipocytes browning, while its effect is limited.

Characterization of Plocamium telfairiae Extract-Functionalized Au Nanostructures and Their Anti-Adipogenic Activity through PLD1

“…Meanwhile, PGC-1a is an electron coactivator regulating transcription factors involved in mitochondrial respiration and biosynthesis and stimulates tricarboxylic acid cycle expression, peroxisomal activity, and mitochondrial fatty acid oxidation. Finally, PRDM16 enhances the expression of genes involved in mitochondrial biosynthesis through interaction with PGC-1a and promotes brown adipogenesis in adipocytes [ 41 , 42 , 43 ]. Here, immunofluorescence screening was performed to confirm mitochondrial biogenesis and UCP-1 expression, which are characteristics of brown adipogenesis.…”

Peritumoral adipose tissue promotes lipolysis and white adipocytes browning by paracrine action

“…Thus, lipolysis and browning induced by hATT-CM would be regulated by pERK. In relation to AKT, recent studies have shown that the phosphorylated form is involved in adipocyte browning, a pathway regulated by insulin ( 60 ). Thus, soluble factors released by peritumoral adipocytes could also induce paracrine browning of adipocytes via AKT and ERK phosphorylation, because hATT-CM induced an increase in pAKT and pERK in mature adipocytes.…”